SGK1 is an inducible serine/threonine kinase that has been implicated in membrane transport processes in epithelial cell. Studies have shown that SGK1 is transcriptionally induced and subject to stimulus-dependent post-translational phosphorylation. Hyperphosphorylation of SGK1 leads to activation of its kinase activity and has been linked to changes in cellular proliferation, survival and intracellular ion and transport processes. Phosphorylation also controls nuclear/cytoplasmic shuttling of SGK1 such that hyperphosphorylation on serine/threonine residues leads to nuclear translocation from the cytosol. Although much progress has been made regarding the role of SGK1 in epithelial cell biology, its role in vascular smooth muscle cell function and in the development of lesion formation in particular is completely unknown. Therefore, this application seeks to define the role of SGK1 in regulation of vascular smooth muscle cell fate, specifically as it relates to growth. In preliminary studies we found that the potent mitogen, PDGF, dramatically and transiently increases SGK1 mRNA expression in vascular smooth muscle cells implicating a role for this kinase in vascular smooth muscle cell growth. We also found that PDGF stimulation is associated with increased phosphorylation of SGK1, suggesting that PDGF may mediate activation of SGK1 kinase activity. Interestingly, immunohistological staining of injured carotid artery revealed that SGK1 is up-regulated in neointimal vascular lesions. [unreadable] [unreadable] In light of these findings, we hypothesize that SGK1 is an important mediator of vascular smooth muscle cell proliferation and that alterations in its expression and/or activity leads to the subsequent development of vascular neointimal lesion formation. We will test this hypothesis in the following aims: (1) to investigate the effects of mitogenic stimuli on SGK1 expression, activity and compartmentalization in VSMC in vitro; (2) to investigate the effect of constitutive SGK1 knockdown and over-expression on regulation of VSMC growth in vitro; (3) to investigate the effect of mechanical vascular injury on SGK1 expression and activity in a rat carotid artery balloon-injury model in vivo. Overall, this series of experiments will provide insight into the role of SGK1 in vascular smooth muscle cell proliferation and provide the basis for future studies to define the role of SGK1 in pathological vascular remodeling. Ultimately, these studies identify SGK1 as a novel therapeutic target for occlusive vascular diseases that occur as a consequence of atherosclerosis, restenosis or hypertension. [unreadable] [unreadable] [unreadable]